ARVO 2025: Association between autosomal dominant Alzheimer's disease and optic nerve head drusen

At ARVO 2025, in Salt Lake City, Utah, Danielle Gauthuer talked about her poster on autosomal dominant Alzheimer's disease in relation to optic nerve head drusen.

Video Transcript:

Editor's note: The below transcript has been lightly edited for clarity.

Danielle Gauthier:

Hello. My name is Danielle Gauthuer, I'm a lab technician with Doheny Eye Institute. I'm also a research fellow with Dr Alfredo Sadun, who is affiliated with UCLA David Geffen School of Medicine. And I'm here today to talk about my poster, which is on autosomal dominant Alzheimer's disease in relation to optic nerve head drusen. Our main thing was we wanted to look to see if optic nerve head drusen is associated with or may be caused by autosomal dominant Alzheimer's disease. So I'll be calling it ADAD. So we had a very rare case of homozygous ADAD, a postmortem tissue that we stained for three types of staining. GFAP, neurofilament protein, and Aβ. So the main thing is, we wanted to see whether or not the neurotoxicity associated with ADAD could cause optic nerve head drusen to form. So that was the main reason why we looked at and stained these three stains.

For instance, GFAP, this is mainly staining glial fibulary acidic proteins. This is associated with astrocytes. Astrocytes tend to come in whenever there's injury to the eye. And so with this stain, we did find that it was positive, and we found it in a heterogeneous pattern. So it's leading us to the idea, or maybe the conclusion, that maybe axonal injury is caused by the inheritance of ADAD. Which, again, it's an Alzheimer's disease, but it's known to come around when you're 30 to 60 [years old], so a lot younger than what you typically are seeing.
So it's a very rare tissue, and that's why we only have one, unfortunately. We hope, maybe in the future, to get more, but it's very rare. So while we have many controls, we only had one tissue to look at.

Then we also looked at neurofilament protein, which stains your axons in neurons. So when we were looking at this, you could see in the neurofilament protein, it's as if there was like a big circle–in neurofilament protein you can think of it as, like the structure, the support structure of the cell. And so in it, typically it should kind of look like lines in the picture, but instead we see like a big circle. That's where the drusen is. So the drusen comes in and causes injury to occur, and it causes the cell to kind of burst. So you see, like a big, like plaque aggregate formed in there. So, you know, okay, this, this is not normal. So again, we saw staining for that. So we are assuming that there is some neurodegeneration or axonal injury. We're not sure the etiology. It's not explained in the literature what causes optic nerve head drusen. So we're starting from, we know that drusen is calcified deposits, but we're not completely sure what causes it. So that was the main point to stain for those two stains.

Then the last one was Aβ, which we saw a strong presence with. And the main thing is we saw amyloid plaques, this accumulates between the cells, and it's formed by when amyloid precursor protein clumps together and accumulates. So we saw that as well. Typically with optic drusen, you see it on the retinal side. So optic nerve had drusen is a bit different. We're seeing this in the like pre-lamina cribrosa, so it's a bit different. And typically, when you're looking at like drusen, you're seeing it being scanned on the OCT, there's not a lot of postmortem tissue staining. Everything when you're being diagnosed with drusen, it's all like OC T based, because you can see it when you're doing a scan of the retina. So typically you'll hear retinal drusen, versus optic nerve head drusen is a bit different. It's more if you were to look at the optic nerve head, it's a little bit more so by the lamina cribrosa, which is where we found the association.

We're not sure whether drusen is associated with ADAD. And that was the main point on why we want to stain, to try to see is there an association. Because our further steps in the future, is to stain for cytochrome c, which it stains essentially for cytochrome c oxidase, which is used in high mitochondrial activity. So we want to know, okay, does ADAD cause this drusen. Which we can't make that conclusion based on just one case, but hopefully in the future, we can get more eyes and do further staining to kind of test whether or not there's a link to it.

I would say that if there were to be in postmortem tissue, drusen found it would be interesting to know whether or not what the disease, like any precursor disease that they had. For instance, it would be interesting to look if someone had drusen in Lebers or drusen in in dominant optic atrophy, because we want to know whether this genetic inheritance of a disease can lead to this, like if there's a neurotoxic link, or a neurodegeneration can cause drusen to form. Because there hasn't been really that association linked yet, because, again, it is difficult to kind of–correlation isn't causation. So you kind of need more tissues to form that link to see if there could be an association. I think this would be great to look at in regular Alzheimer's disease eyes. But again, we have to find that drusen first. We were lucky in that in the first slice of this tissue, we saw the drusen immediately, but again, you need to see the drusen to be able to test and stain whether there's a link to it.